Michael Rosenblatt was host for the meeting and introduced his guest, Robert Plenge, MD. PhD.   Dr. Plenge received his MD and PhD degrees from Case Western, his PhD research being in human genetics with Hunt Willard.  He was then a resident in internal medicine at UCSF followed by a fellowship in rheumatology at the Brigham.  Dr. Plenge then joined the group of David Altschuler at the Broad as a post-doctoral fellow.  In 2008 he was appointed and Assistant Professor of Medicine in the Division of Rheumatology , Immunology and Allergy at the Brigham, soon rising to Director of Genetics and Genomics within the Division and appointment as an Associate Member of the Broad.  In 2014 he joined Merck Research Laboratories as Vice President and Head of Genetics and Pharmacogenomics (“GpGx”).

Dr. Plenge began his presentation by emphasizing that although the roles of genetics in many human diseases has of course long been appreciated, Merck’s newly launched Genetics and Pharmacogenomics Program has a revisionist conceptual foundation.  Retrospective analysis of drug failures has revealed the major influence of two factors on the success of Phase II and IIa trials:  existing information of genetic linkage of the target to disease indication, and the availability of efficacy biomarkers at the commencement of the trial.  Dr. Plenge went to describe how the Merck GpGx strategy aims to determine dose-response parameters not in the clinical trial itself, but at the time of target identification and validation.  It is envisioned that this will be done be analyzing a series of alleles whose revealed biological functions will allow estimation of the “apparent efficacy” of the lead compound’s response curve.  Dr. Plenge described this strategy using the example of the TYK2 gene and rheumatoid arthritis.     

   Pedigree analysis of rare families with loss of TYK2 revealed a protective effect against RA.  Laboratory loss of function studies were undertaken and a Phenome-Wide Association Study in ca. 30,000 EMR patients was also performed to assess the pleiotropic range of TYK2 loss, revealing RA as the highest association, RA-related disorders almost as high, and a cluster of skin and subcutaneous autoimmune disorders also showing statistically elevated association.  From the degree of RA protection in TYK2 -/- vs. +/- subjects and the existence of immunodeficiency in the homozygotes, a therapeutic window was deduced for a (theoretical) drug. 

   Dr. Plenge concluded by summarizing the company’s aspirations with the GpGx approach, which will involve working with various centers and genomic information:  1] the NIH >100,000 patient complex trait database;  2] major sequencing centers to uncover rare, highly penetrant mutations;  3] sequences of consanguineous Amish, Finnish and other ethnic families;  4] analysis of sequence data (Partners HealthCare, Vanderbilt, 23 & Me), or in due course complete genomes, of patients for whom EMR data are available, to assess pleiotropy and Adverse Drug Effects; and 5] high-throughput functional studies (both internal and academic/biotech company collaborations) to define underlying biology and inform design of drug screens.